Factors influencing genetic instability in adult B-cell acute lymphoblastic leukemias (B-OBL)

Acute B-cell lymphoblastic leukemia (B-OBL) is a biologically diverse group of diseases that underlie specific genetic changes that result in abnormal differentiation and proliferation of the hematopoietic cell. In recent years, there has been great progress in the treatment of B-OBL, especially in children. Unfortunately, the results of treatment in adults are still unsatisfactory. One of the reasons for this may be the presence of two genetic subtypes of leukemia with a very high risk of disease progression in more than half of adults with B-OBL - BCR-ABL1 positive and BCR-ABL1-like. Both leukemia subtypes, despite the different genetic changes occurring in them, show a similar gene expression profile, which consequently leads to the activation of the JAK-STAT pathway. Recent reports indicate that both BCR-ABL1-positive B-OBL and BCR-ABL1-like may share a similar mechanism responsible for disease progression, which is related to an unfavorable prognosis. Both BCR-ABL1-positive and BCR-ABL1-like leukemia have been shown to be characterized by a high percentage of specific genetic mutations (changes in copy number of DNA fragments; CNAs), mainly deletions. Their presence is probably due to abnormal activity of some cellular enzymes. The complex of recombinases - RAGs and proteins from the APOBEC family, including cytidine deaminase AID, are enzymes involved in a very important physiological process, namely the production of functional antibodies and the formation of their diversity in contact with the pathogen. The activity of both enzymes is characteristic of the lymphoid tissues from which B-OBL is derived. However, it is a double-edged sword, which, on the one hand, allows the body to produce antibodies that protect us against the threat of microbes, and on the other hand, it can cause genetic changes leading to the formation and progression of cancer. Therefore, the project focuses on endogenous genomic mutators such as RAGs, AID, APOBEC3A, APOBEC3B. For this purpose, various methods of molecular biology will be used, including DNA sequencing and gene expression analysis. The project aims to elucidate the molecular basis leading to a poor prognosis in adults with B-OBL, namely the phenomena of genetic instability mediated by RAGs and proteins from the APOBEC family. During genetic instability, mutations accumulate, favoring the selection of leukemic clones and causing disease progression. Despite the great progress in this field of science, there is still not enough knowledge about it. The above research may also translate into other areas of oncology, constituting a starting point and inspiration to repeat similar research in other disease entities.